Lenalidomide and Combination Chemotherapy (DA-EPOCH-R) in Treating Patients With MYC-Associated B-Cell Lymphomas

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of lenalidomide when added to dose-adjusted
(DA)-etoposide, prednisone, vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide,
rituximab (EPOCH-R) (hereby termed "DA-EPOCH-RR") in patients with double hit lymphoma (DHL)
lymphomas. (Phase I) II. To determine the 1- and 2-year progression free survival (PFS) of
DA-EPOCH-RR in patients with DHL lymphomas. (Phase II)

SECONDARY OBJECTIVES:

I. Overall response rate, complete response, and duration of response. II. Quality of life
(QOL) measures using standardized scales. III. Toxicity assessment using version 4.0 of the
National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE)
criteria.

IV. Overall survival (OS) at 1 and 2 years.

OUTLINE: This is a phase I, dose-escalation study of lenalidomide followed by a phase II
study.

INDUCTION PHASE: Patients receive lenalidomide orally (PO) daily on days 1-14. Treatment
repeats every 21 days for 6 courses in the absence of disease progression or unacceptable
toxicity.

DA-EPOCH-R: Patients receive etoposide intravenously (IV) continuously on days 1-4,
prednisone PO twice daily (BID) on days 1-5, vincristine sulfate IV continuously on days 1-4,
doxorubicin hydrochloride IV continuously on days 1-4, cyclophosphamide IV over 15 minutes on
day 5, and rituximab IV over 4 hours on day 1 (per institutional guidelines). Treatment
repeats every 21 days for 6 courses in the absence of disease progression or unacceptable
toxicity.

CONSOLIDATION PHASE: Patients who are transplantation (hematopoietic stem cell transplant
[HSCT])-eligible receive BCNU, etoposide, cytarabine, and melphalan (BEAM)-conditioning
regimen followed by autologous (auto)-HSCT or HSCT at the discretion of the treating
physician. Patients who do not undergo HSCT in first remission receive lenalidomide
maintenance for 12 months.

After completion of study treatment, patients are followed up for every 3 months for 1 year,
every 4 months for 1 year, and then periodically for 1 year.

Inclusion Criteria

1. B-cell lymphoma with comprehensive immunohistochemistry (IHC) panel establishing
lineage (CD20, CD3) and cell of origin (CD10, BCL6 and MUM1) in addition to
proliferative/prognostic markers (Ki-67, C-myc and BCL2). DHL will be identified using
cytogenetics and/or immunohistochemistry as detailed in section 4.1.2 below.

2. To define DHL, patients must have evidence of C-myc [defined as: Cytogenetic evidence
(FISH or karyotype) of C-myc breaks (Increased copy number in itself is not considered
positivity for C-myc) OR Positive IHC defined as >40% of the lymphoma cells staining
for C-myc] PLUS either:

1. Breaks in BCL-2 via cytogenetic studies or

2. BCL-2 immunopositivity in >70% of lymphoma cells.

3. Patients are allowed to have received radiotherapy before enrollment if radiation was
given to alleviate pain and/or neurologic compromise as long as there remains areas of
measurable disease present. Further, at the investigator's discretion and for patients
who are unstable, one cycle of R-CHOP is allowed prior to enrollment but no more than
one cycle. For purposes of this trial, prednisone or other corticosteroids used for
non-lymphomatous conditions will be allowed. In addition, a prior/recent short course
(< 2 weeks) of steroids for symptom relief of lymphoma-related symptoms will be
allowed.

4. AST and ALT < 3 x upper limit of normal (ULN), and total bilirubin <1.5 x ULN (with
exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver
involvement with NHL or stable chronic liver disease per investigator assessment).

5. Patients must have adequate renal function by virtue of GFR > 50 ml/minute using
Cockroft-Gault formula.

6. Patients must have adequate bone marrow function (platelets >100,000 and ANC >1,200).
Patients with bone marrow involvement are allowed at the investigator's discretion
regardless of cytopenias.

7. ECOG PS 0-2.

8. Age ≥ 18 years.

9. All study participants must be registered into the mandatory lenalidomide REMS®
program, and be willing and able to comply with the requirements of the REMS® program.

10. Females of reproductive potential must adhere to the scheduled pregnancy testing as
required in the lenalidomide REMS® program. (Please see study schema for further
details)

11. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients
intolerant to ASA may use warfarin or low molecular weight heparin).

12. Ability to read, understand, and sign a written informed consent approved by each
institutional IRB. Alternatively, patients with legal guardians who can read,
understand, and sign written informed consent may also enroll.

Exclusion Criteria

1. Prior therapy for lymphoma

2. Known CNS involvement

3. Known HIV positive status

4. Pregnant females

5. Burkitt and/or precursor lymphoblastic leukemia/lymphoma.

6. Prior pomalidomide exposure

7. Known hypersensitivity to lenalidomide or thalidomide

8. The development of erythema nodosum if characterized by a desquamating rash while
taking thalidomide or similar drugs.

9. Subjects who have currently active hepatic or biliary disease (with exception of
patients with Gilbert's syndrome, asymptomatic gallstones, liver involvement with NHL
or stable chronic liver disease per investigator assessment).

10. Treatment with any known non-marketed drug substance or experimental therapy within 4
weeks prior to enrollment, or currently participating in any other interventional
clinical study for NHL or any other illness (except observational, prevention, and/or
registry trials).

11. No current malignancy. Subjects who have been free of malignancy for at least 2 years,
or have a history of completely resected non-melanoma skin cancer, or successfully
treated in situ carcinoma (any site) are eligible. Women with a history of cervical
cancers are allowed.

12. Chronic or current infectious disease requiring systemic antibiotics, antifungal, or
antiviral treatment such as, but not limited to, chronic renal infection, chronic
chest infection with bronchiectasis, tuberculosis and active Hepatitis C.

13. History of significant cerebrovascular disease in the past 3 months or ongoing event
with active symptoms or sequelae.

14. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In
addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB
DNA test will be performed and if positive, the subject will be excluded if unable to
tolerate and/or receive anti-Hepatitis-B therapy. Positive serology because of prior
vaccination is allowed.

15. Positive serology for hepatitis C (HC) defined as a positive test for HCAb.

16. Inability to comply with study or follow-up testing and procedures.